Ningalin B analogs employable for reversing multidrug resistance
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Abstract
Anlogs of ningalin B lacking inherent cytotoxic activity may be employed to reverse multi-drug resistant (MDR) phenotype and to resensitize transformed cells, including a human colon cancer cell line (HCT116/VM46), with respect to a variety of cytotoxic agents, e.g., vinblastine and doxorubicin. In many instances, resensitization is achieved at lower doses than the prototypical agent verapamil. Total synthesis of ningalin B and its analogs was achieved using a concise, efficient approach based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine→1,2-diazine→pyrrole) ideally suited for construction of the densely functionalized pyrrole core found in the natural product is detailed.
8 Citations
20 Claims
- 1. A compound represented by the following structure:
- 4. A compound represented by the following structure:
- 9. An analog of ningalin B represented by the following structure:
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10. A synthetic process comprising the following step:
cyclizing a precursor compound with an excess of Eaton'"'"'s acid at room temperature under reaction conditions for producing an analog of ningalin B, the precursor compound, the analog of ningalin B, and the cyclization reaction being represented as follows;
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11. A process for P-gp mediated reversing multidrug resistance in a cancer cell comprising the step of
contacting said cancer cell with a concentration sufficient for reversing said P-gp mediated multidrug resistance of a compound selected from a group consisting of compounds represented by the following structures:
Specification